Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof

ABSTRACT

A process for preparing xanthine phosphodiesterase V inhibitors, and compounds utilized in said process. The process includes a five-step methodology for efficient synthesis of Compound 5 without intermediate purifications or separations, a dihalogenation step to synthesize Compound 7, and a coupling reaction to produce Compound 9.

CROSS-REFERENCE TO RELATED PATENT APPLICATION

This is a Continuation of U.S. patent application Ser. No. 10/449,526,filed May 30, 2004, which application is incorporated herein in itsentirety by reference, and which application in turn claims priorityunder 35 USC section 119(e) to U.S. Provisional Application Ser. No.60/384,478, filed May 31, 2002, which application is also incorporatedby reference herein as if fully set forth.

FIELD OF THE INVENTION

The invention relates to a process for preparing polycyclic xanthinephosphodiesterase V (“PDE V”) inhibitors. The invention further relatesto compounds useful for preparing PDE V inhibitors.

BACKGROUND

Processes for preparing PDE V inhibitor compounds can be found in U.S.Pat. No. 6,207,829, U.S. Pat. No. 6,066,735, U.S. Pat. No. 5,955,611,U.S. Pat. No. 5,939,419, U.S. Pat. No. 5,393,755, U.S. Pat. No.5,409,934, U.S. Pat. No. 5,470,579, U.S. Pat. No. 5,250,534, WO02/24698, WO 99/24433, WO 93/23401, WO 92/05176, WO 92/05175, EP 740,668and EP 702,555. One type of PDE V inhibitor compound contains a xanthinefunctionality in its structure. Xanthines can be prepared as describedby Peter K. Bridson and Xiaodong Wang in 1-Substituted Xanthines,Synthesis, 855 (July, 1995), which is incorporated herein by referencein its entirety. WO 02/24698, which is incorporated herein by referencein its entirety, teaches a class of xanthine PDE V inhibitor compoundsuseful for the treatment of impotence. A general process disclosedtherein for preparing xanthine PDE V inhibitor compounds having theformula (I) follows:

-   -   (i) reacting a compound having the formula (III) with an alkyl        halide in the presence of a base (introduction of R^(II) or a        protected form of R^(II));    -   (ii) (a) debenzylating and then (b) alkylating the compound        resulting from step (i) with an alkyl halide, XCH₂R^(III);    -   (iii) (a) deprotonating and then (b) halogenating the compound        resulting from step (ii);    -   (iv) reacting the compound resulting from step (iii) with an        amine having the formula R^(IV)NH₂; and    -   (v) removing a protecting portion of R^(II), if present, on the        compound resulting from step (iv) to form the compound having        the formula (I).

R^(I), R^(II), R^(III) and R^(IV) correspond to R¹, R², R³ and R⁴,respectively, in WO 02/24698, and are defined therein. WO 02/24698(pages 44 and 68-73) also teaches a synthesis for the following xanthinecompound (identified therein as Compound 13 or Compound 114 of TableII):1-ethyl-3,7-dihydro-8-[(1R,2R)-(hydroxycyclopentyl)amino]-3-(2-hydroxyethyl)-7-[(3-bromo-4-methoxyphenyl)methyl]-1H-purine-2,6-dione:

It would be beneficial to provide an improved process for preparingpolycyclic xanthine PDE V inhibitor compounds. It would further bebeneficial if the process provided high yields without the need forchromatographic purification. It would still further be beneficial ifthe process provided compounds of high thermodynamic stability. It wouldbe still further beneficial to provide intermediate compounds that canbe used in the improved process. The invention seeks to provide theseand other benefits, which will become apparent as the descriptionprogresses.

SUMMARY OF THE INVENTION

One aspect of the invention is a method for preparing a Compound 13,comprising:

-   -   (a) reacting glycine ethyl ester or a salt thereof with

-   -    to form

-   -    wherein Et is CH₃CH₂—,    -   (b) reducing

-   -    to form a Compound 1:

-   -   (c) reacting cyanamide with an excess of triethylorthoformate to        form a Compound 2:

-   -   (d) reacting the Compound 2 with the Compound 1 to form a        Compound 3:

-   -   (e) reacting the Compound 3 with a base to form a Compound 4:

-   -   (f) reacting the Compound 4 with R²NHCO₂R¹ in the presence of a        metallic base to form a Compound Salt 5K:

-   -    wherein M⁺ is a metal ion,    -   (g) optionally, reacting the Compound Salt 5K with an acid to        form a Compound 5:

-   -   (h) reacting the Compound Salt 5K or the Compound 5 with BrCH₂L        in the presence of a phase transfer catalyst to form a Compound        6:

wherein L is R³ or a protected form of R³ comprising R³ with aprotective substituent selected from the group consisting of acetate,propionate, pivaloyl, —OC(O)R⁵, —NC(O)R⁵ and —SC(O)R⁵ group, wherein R⁵is H or C₁₋₁₂ alkyl;

-   -   (i) dihalogenating the Compound 6 to form a Compound 7:

-   -   (j) reacting the Compound 7 with R⁴NH₂, and adding a base        thereto, to form a Compound 9:

-   -   (k) (i) when L is R³, the Compound 9 is a Compound 13, and        -   (ii) when L is a protected form of R³, reacting the Compound            9 with a base to form the Compound 13:

wherein,

-   -   R¹, R² and R³ are each independently selected from the group        consisting of:    -   H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, allyl,        —OR⁵,    -   —C(O)OR⁵, —C(O)R⁵, —C(O)N(R⁵)₂, —NHC(O)R⁵ and —NHC(O)OR⁵,        wherein each R⁵ is independently H or alkyl;        -   provided that R² and R³ are not both —H;        -   R⁴ is an alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,            aryl or heteroaryl group;        -   wherein R¹, R², R³ and R⁴ are optionally substituted with            one or more moieties independently selected from the group            consisting of: alkyl, cycloalkyl, alkenyl, cycloalkenyl,            alkynyl, aryl, heteroaryl, heterocycloalkyl, halo, thio,            nitro, oximino, acetate, propionate, pivaloyl, —OC(O)R⁵,            —NC(O)R⁵ or —SC(O)R⁵, —OR⁵⁰, —NR⁵⁰R⁵¹, —C(O)OR⁵⁰, —C(O)R⁵⁰,            —SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, —NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═NOR⁵⁰,            ═NCN, ═C(halo)₂, ═S, ═O, —C(O)N(R⁵⁰R⁵¹), —OC(O)R⁵⁰,            —OC(O)N(R⁵⁰R⁵¹), —N(R⁵²)C(O)(R⁵⁰), —N(R⁵²)C(O)OR⁵⁰ and            —N(R⁵²)C(O)N(R⁵⁰R⁵¹), wherein each R⁵ is independently H or            alkyl and R⁵⁰, R⁵¹ and R⁵² are each independently selected            from the group consisting of: H, alkyl, cycloalkyl,            heterocycloalkyl, heteroaryl and aryl, and when chemically            feasible, R⁵⁰ and R⁵¹ can be joined together to form a            carbocyclic or heterocyclic ring;        -   Et is CH₃CH₂—;        -   Hal is a halogen group; and        -   L is a protected form of R³ comprising R³ with a protective            substituent selected from the group consisting of acetate,            propionate, pivaloyl, —OC(O)R⁵, —NC(O)R⁵ and —SC(O)R⁵ group,            wherein R⁵ is H or C₁₋₁₂ alkyl.

A further understanding of the invention will be had from the followingdetailed description of the invention.

DETAILED DESCRIPTION

Definitions and Usage of Terms

The following definitions and terms are used herein or are otherwiseknown to a skilled artisan. Except where stated otherwise, thedefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“alkoxy,” etc.

Unless otherwise known, stated or shown to be to the contrary, the pointof attachment for a multiple term substituent (two or more terms thatare combined to identify a single moiety) to a subject structure isthrough the last named term of the multiple term substituent. Forexample, a cycloalkylalkyl substituent attaches to a targeted structurethrough the latter “alkyl” portion of the substituent (e.g.,structure-alkyl-cycloalkyl).

The identity of each variable appearing more than once in a formula maybe independently selected from the definition for that variable, unlessotherwise indicated.

Unless stated, shown or otherwise known to be the contrary, all atomsillustrated in chemical formulas for covalent compounds possess normalvalencies. Thus, hydrogen atoms, double bonds, triple bonds and ringstructures need not be expressly depicted in a general chemical formula.

Double bonds, where appropriate, may be represented by the presence ofparentheses around an atom in a chemical formula. For example, acarbonyl functionality, —CO—, may also be represented in a chemicalformula by —C(O)— or —C(═O)—. Similarly, a double bond between a sulfuratom and an oxygen atom may be represented in a chemical formula by—SO—, —S(O)— or —S(═O)—. One skilled in the art will be able todetermine the presence or absence of double (and triple bonds) in acovalently-bonded molecule. For instance, it is readily recognized thata carboxyl functionality may be represented by —COOH, —C(O)OH, —C(═O)OHor —CO₂H.

The term “substituted,” as used herein, means the replacement of one ormore atoms or radicals, usually hydrogen atoms, in a given structurewith an atom or radical selected from a specified group. In thesituations where more than one atom or radical may be replaced with asubstituent selected from the same specified group, the substituents maybe, unless otherwise specified, either the same or different at everyposition. Radicals of specified groups, such as alkyl, cycloalkyl,heterocycloalkyl, aryl and heteroaryl groups, independently of ortogether with one another, may be substituents on any of the specifiedgroups, unless otherwise indicated.

The term “optionally substituted” means, alternatively, not substitutedor substituted with the specified groups, radicals or moieties. Itshould be noted that any atom with unsatisfied valences in the text,schemes, examples and tables herein is assumed to have the hydrogenatom(s) to satisfy the valences.

The term “chemically-feasible” is usually applied to a ring structurepresent in a compound and means that the ring structure (e.g., the 4- to7-membered ring, optionally substituted by . . . ) would be expected tobe stable by a skilled artisan.

The term “heteroatom,” as used herein, means a nitrogen, sulfur oroxygen atom. Multiple heteroatoms in the same group may be the same ordifferent.

As used herein, the term “alkyl” means an aliphatic hydrocarbon groupthat can be straight or branched and comprises 1 to about 24 carbonatoms in the chain. Preferred alkyl groups comprise 1 to about 15 carbonatoms in the chain. More preferred alkyl groups comprise 1 to about 6carbon atoms in the chain. “Branched” means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkylchain. The alkyl can be substituted by one or more substituentsindependently selected from the group consisting of halo, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂ (which alkyls can be the same or different),carboxy and —C(O)O-alkyl. Non-limiting examples of suitable alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group (straight or branchedcarbon chain) comprising one or more double bonds in the chain and whichcan be conjugated or unconjugated. Useful alkenyl groups can comprise 2to about 15 carbon atoms in the chain, preferably 2 to about 12 carbonatoms in the chain, and more preferably 2 to about 6 carbon atoms in thechain. The alkenyl group can be substituted by one or more substituentsindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano and alkoxy. Non-limiting examples of suitable alkenylgroups include ethenyl, propenyl, n-butenyl, 3-methylbut-enyl andn-pentenyl.

Where an alkyl or alkenyl chain joins two other variables and istherefore bivalent, the terms alkylene and alkenylene, respectively, areused.

“Alkoxy” means an alkyl-O-group in which the alkyl group is aspreviously described. Useful alkoxy groups can comprise 1 to about 12carbon atoms, preferably 1 to about 6 carbon atoms. Non-limitingexamples of suitable alkoxy groups include methoxy, ethoxy andisopropoxy. The alkyl group of the alkoxy is linked to an adjacentmoiety through the ether oxygen.

The term “cycloalkyl” as used herein, means an unsubstituted orsubstituted, saturated, stable, non-aromatic, chemically-feasiblecarbocyclic ring having preferably from three to fifteen carbon atoms,more preferably, from three to eight carbon atoms. The cycloalkyl carbonring radical is saturated and may be fused, for example, benzofused,with one to two cycloalkyl, aromatic, heterocyclic or heteroaromaticrings. The cycloalkyl may be attached at any endocyclic carbon atom thatresults in a stable structure. Preferred carbocyclic rings have fromfive to six carbons. Examples of cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or thelike.

The term “hydrocarbon,” as used herein, means a compound, radical orchain consisting of only carbon and hydrogen atoms, including aliphatic,aromatic, normal, saturated and unsaturated hydrocarbons.

The term “alkenyl,” as used herein, means an unsubstituted orsubstituted, unsaturated, straight or branched, hydrocarbon chain havingat least one double bond present and, preferably, from two to fifteencarbon atoms, more preferably, from two to twelve carbon atoms.

The term “cycloalkenyl,” as used herein, means an unsubstituted orsubstituted, unsaturated carbocyclic ring having at least one doublebond present and, preferably, from three to fifteen carbon atoms, morepreferably, from five to eight carbon atoms. A cycloalkenyl goup is anunsaturated carbocyclic group. Examples of cycloalkenyl groups includecyclopentenyl and cyclohexenyl.

“Alkynyl” means an aliphatic hydrocarbon group comprising at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 10 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. Non-limiting examples ofsuitable alkynyl groups include ethynyl, propynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, and decynyl. The alkynyl group may besubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of alkyl, aryl and cycloalkyl.

The term “aryl,” as used herein, means a substituted or unsubstituted,aromatic, mono- or bicyclic, chemically-feasible carbocyclic ring systemhaving from one to two aromatic rings. The aryl moiety will generallyhave from 6 to 14 carbon atoms with all available substitutable carbonatoms of the aryl moiety being intended as possible points ofattachment. Representative examples include phenyl, tolyl, xylyl,cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, or the like. Ifdesired, the carbocyclic moiety can be substituted with from one tofive, preferably, one to three, moieties, such as mono- throughpentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy,amino, monoalkylamino, dialkylamino, or the like.

“Heteroaryl” means a monocyclic or multicyclic aromatic ring system ofabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the atoms in the ring system is/are atomsother than carbon, for example nitrogen, oxygen or sulfur. Mono- andpolycyclic (e.g., bicyclic) heteroaryl groups can be unsubstituted orsubstituted with a plurality of substituents, preferably, one to fivesubstituents, more preferably, one, two or three substituents (e.g.,mono- through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy,alkoxy, phenoxy, amino, monoalkylamino, dialkylamino, or the like).Typically, a heteroaryl group represents a chemically-feasible cyclicgroup of five or six atoms, or a chemically-feasible bicyclic group ofnine or ten atoms, at least one of which is carbon, and having at leastone oxygen, sulfur or nitrogen atom interrupting a carbocyclic ringhaving a sufficient number of pi (π) electrons to provide aromaticcharacter. Representative heteroaryl (heteroaromatic) groups arepyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl,thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl,pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl groups.

The term “heterocycloalkyl,” as used herein, means an unsubstituted orsubstituted, saturated, chemically-feasible cyclic ring system havingfrom three to fifteen members, preferably, from three to eight members,and comprising carbon atoms and at least one heteroatom as part of thering.

The term “heterocyclic ring” or “heterocycle,” as used herein, means anunsubstituted or substituted, saturated, unsaturated or aromatic,chemically-feasible ring, comprised of carbon atoms and one or moreheteroatoms in the ring. Heterocyclic rings may be monocyclic orpolycyclic. Monocyclic rings preferably contain from three to eightatoms in the ring structure, more preferably, five to seven atoms.Polycyclic ring systems consisting of two rings preferably contain fromsix to sixteen atoms, most preferably, ten to twelve atoms. Polycyclicring systems consisting of three rings contain preferably from thirteento seventeen atoms, more preferably, fourteen or fifteen atoms. Eachheterocyclic ring has at least one heteroatom. Unless otherwise stated,the heteroatoms may each be independently selected from the groupconsisting of nitrogen, sulfur and oxygen atoms.

The term “carbocyclic ring” or “carbocycle,” as used herein, means anunsubstituted or substituted, saturated, unsaturated or aromatic (e.g.,aryl), chemically-feasible hydrocarbon ring, unless otherwisespecifically identified. Carbocycles may be monocyclic or polycyclic.Monocyclic rings, preferably, contain from three to eight atoms, morepreferably, five to seven atoms. Polycyclic rings having two rings,preferably, contain from six to sixteen atoms, more preferably, ten totwelve atoms, and those having three rings, preferably, contain fromthirteen to seventeen atoms, more preferably, fourteen or fifteen atoms.

The term “hydroxyalkyl,” as used herein, means a substituted hydrocarbonchain preferably an alkyl group, having at least one hydroxy substituent(-alkyl-OH). Additional substituents to the alkyl group may also bepresent. Representative hydroxyalkyl groups include hydroxymethyl,hydroxyethyl and hydroxypropyl groups.

The terms “Hal,” “halo,” “halogen” and “halide,” as used herein, mean achloro, bromo, fluoro or iodo atom radical. Chlorides, bromides andfluorides are preferred halides.

The term “thio,” as used herein, means an organic acid radical in whichdivalent sulfur has replaced some or all of the oxygen atoms of thecarboxyl group. Examples include —R⁵³C(O)SH, —R⁵³C(S)OH and —R⁵³C(S)SH,wherein R⁵³ is a hydrocarbon radical.

The term “nitro,” as used herein, means the —N(O)₂ radical.

The term “allyl,” as used herein, means the —C₃H₅ radical.

The term “phase transfer catalyst,” as used herein, means a materialthat catalyzes a reaction between a moiety that is soluble in a firstphase, e.g., an alcohol phase, and another moiety that is soluble in asecond phase, e.g., an aqueous phase.

The following abbreviations are used in this application: EtOH isethanol; Me is methyl; Et is ethyl; Bu is butyl; n-Bu is normal-butyl,t-Bu is tert-butyl, OAc is acetate; KOt-Bu is potassium tert-butoxide;NBS is N-bromo succinimide; NMP is 1-methyl-2-pyrrolidinone; DMA isN,N-dimethylacetamide; n-Bu₄NBr is tetrabutylammonium bromide; n-Bu₄NOHis tetrabutylammonium hydroxide, n-Bu₄NH₂SO₄ is tetrabutylammoniumhydrogen sulfate, and equiv. is equivalents.

In certain of the chemical structures depicted herein, certain compoundsare racemic, i.e., a mixture of dextro- and levorotatory opticallyactive isomers in equal amounts, the resulting mixture having no rotarypower.

General Synthesis

One aspect of the invention comprises a general synthesis of xanthinesbased on a one-pot, five-step sequence from cyanamide and N-aryl glycineester. Compound 1 can be prepared from glycine ethyl ester or a saltthereof (e.g., hydrochloric or sulfuric acid salt) and an aromaticaldehyde. As shown in Scheme I below, Compound 1 is prepared fromglycine ethyl ester hydrochloride and an aromatic aldehyde. Compound 2is prepared by reacting cyanamide with an excess oftriethylorthoformate. Compound 3 is prepared by reacting Compound 2 withCompound 1. Compound 3 is converted into Compound 4 by reacting it witha base (e.g., potassium tert-butoxide). Compound 4 is reacted with aN—R²-substituted carbamate (e.g., urethane) in the presence of a base toobtain Compound Salt 5K. Based on the N—R²-substituent of the carbamateused, a desired N-1-R²-substituted xanthine Compound Salt 5K isobtained. Compound Salt 5K is then N-3-L-substituted with an L-halideusing a phase transfer catalyst to provide a tri-substituted (R¹, R² andL) xanthine Compound 6. Alternatively, Compound Salt 5K can beneutralized to Compound 5, which can then be selectively N-L-substitutedto provide Compound 6. A selective dihalogenation of Compound 6 leads toa dihalo Compound 7, which is then coupled with an R⁴-substituted amine,followed by an addition of a base (e.g., sodium bicarbonate), to providea tetrasubstituted (R¹, R², R³ and R⁴) xanthine Compound 13 when L isthe same as R³. If L is a protected form of R³, intermediate Compound 9is deprotected with a base (e.g., tetrabutylammonium hydroxide) toprovide the tetrasubstituted (R¹, R², R³ and R⁴) xanthine Compound 13.Scheme I depicts this process:

wherein,

-   -   R¹, R² and R³ are each independently selected from the group        consisting of:    -   H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, allyl,        —OR⁵,    -   —C(O)OR⁵, —C(O)R⁵, —C(O)N(R⁵)₂, —NHC(O)R⁵ and —NHC(O)OR⁵,        wherein each R⁵ is independently H or alkyl;        -   provided that R² and R³ are not both —H;        -   R⁴ is an alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,            aryl or heteroaryl group;        -   wherein R¹, R², R³ and R⁴ are optionally substituted with            moieties independently selected from the group consisting            of: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,            heteroaryl, heterocycloalkyl, halo, thio, nitro, oximino,            acetate, propionate, pivaloyl, —OC(O)R⁵, —NC(O)R⁵ or            —SC(O)R⁵, —OR⁵⁰, —NR⁵⁰ R⁵¹, —C(O)OR⁵⁰, —C(O)R⁵⁰, —SO₀₋₂R⁵⁰,            —SO₂NR⁵OR⁵¹, —NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═NOR⁵⁰, ═NCN,            ═C(halo)₂, ═S, ═O, —C(O)N(R⁵⁰R⁵¹), —OC(O)R⁵⁰,            —OC(O)N(R⁵⁰R⁵¹), —N(R⁵²)C(O)(R⁵⁰), —N(R⁵²)C(O)OR⁵⁰ and            —N(R⁵²)C(O)N(R⁵⁰R⁵¹), wherein each R⁵ is independently H or            alkyl and R⁵⁰, R⁵¹ and R⁵² are each independently selected            from the group consisting of: H, alkyl, cycloalkyl,            heterocycloalkyl, heteroaryl and aryl;    -   Hal is a halogen group;    -   L is R³ or a protected form of R³ comprising R³ with a        protective substituent selected from the group consisting of        acetate, propionate, pivaloyl, —OC(O)R⁵, —NC(O)R⁵ and —SC(O)R⁵        group, wherein R⁵ is H or alkyl; and    -   M⁺ is a metal ion.

While some compounds are shown in Scheme I as non-isolatedintermediates, it is understood that they can be isolated using routinechemistry techniques.

Preferred embodiments of the invention utilize compounds with thefollowing R¹, R², R³ and R⁴ radicals:

R¹ is preferably alkyl, aryl, heteroaryl, —OR⁵, —C(O)OR⁵, —C(O)R⁵ or—C(O)N(R⁵)₂, wherein R⁵is H or alkyl. Each R¹ group is optionallysubstituted as defined above. More preferably, R¹ is —OR⁵, wherein R⁵ isH or alkyl. Even more preferably, R¹ is alkoxy, such as methoxy.

R² is preferably C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, aryl or heteroaryl. EachR² group is optionally substituted as defined above. More preferably, R²is C₁₋₆ alkyl, optionally substituted as defined above. Even morepreferably, R² is ethyl.

R³ is preferably C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, allyl,—NHC(O)R⁵ or —NHC(O)OR⁵, wherein R⁵ is H or C₁₋₁₂ alkyl. Each R³ groupis optionally substituted as defined above. More preferably, R³ is C₁₋₆alkyl, optionally substituted with one of the groups defined above. Evenmore preferably, R³ is C₁₋₆ alkyl, substituted with —OR⁵⁰, wherein R⁵⁰is H, such as hydroxymethyl.

R⁴ is preferably C₁₋₁₂ alkyl, C₃₋₈ cycloalkyl, C₅₋₈ cycloalkenyl,heterocycloalkyl, aryl or heteroaryl. Each R⁴ group is optionallysubstituted as defined above. More preferably, R⁴ is C₃₋₈ cycloalkyl,optionally substituted as defined above. Even more preferably, R⁴ isC₄₋₇ cycloalkyl, substituted with —OR⁵⁰, wherein R⁵⁰ is defined asabove. For example, R⁴ can be 2-hydroxy cyclopentyl.

In some embodiments of the invention, L is the same as R³. In otherembodiments of the invention, L is a protected form of R³, in which casethe protective substituent on R³ is preferably an acetate, propionate,pivaloyl, —OC(O)R⁵, —NC(O)R⁵ or —SC(O)R⁵ group, wherein R⁵ is H or C₁₋₁₂alkyl.

Hal is preferably chlorine, bromine and fluorine. More preferably, Halis chlorine or bromine. Even more preferably, Hal is bromine.

M⁺ is, preferably, an alkali metal or alkaline earth metal ion. Morepreferably, M⁺ is a potassium or sodium ion.

Compound 1 can be prepared by reacting about equimolar amounts ofp-anisaldehyde and glycine ethyl ester hydrochloride (or its free form)in the presence of a base (e.g., potassium carbonate, sodium carbonate,sodium bicarbonate, potassium butoxide, or the like) and in an alcoholicsolvent (e.g., ethanol, isopropanol, or the like). Preferably, up toabout 2 moles (e.g., about 1.3-1.5 moles) of glycine ethyl esterhydrochloride and up to about 2 moles (e.g., about 1 mole) of inorganicsalt can each be used per mole of p-anisaldehyde. The reaction proceedsthrough an intermediate imine (not shown), which is reduced with areducing agent (e.g., NaBH₄, catalytic hydrogenation, H₂/Pd/C, or thelike), preferably, a borohydride reducing agent. The reaction can be runat room temperature. Preferably, the reaction is run at about 20-45° C.,more preferably, about 30-40° C. At the end of the reaction, Compound 1is isolated in a solution form in an organic solvent (e.g., toluene),and used as such for the next step.

Compound 2 is N-cyanomethanimidic acid ethyl ester, and is prepared byreacting cyanamide with an excess of triethylorthoformate. Preferably,from about 1.2 to about 1.5 moles of triethylorthoformate (e.g., 1.33moles) are reacted with about 1 mole of cyanamide. Preferably, thereaction mixture is gradually heated up to about 85-95° C. for about 2hours. Compound 2 is not isolated, and is used in-situ for the nextstep.

The structure of Compound 3 is novel. An equimolar reaction mixture ofCompound 2 (obtained in-situ above) is added to a solution of Compound 1in an anhydrous, ethereal organic solvent (e.g., tetrahydrofuran(“THF”), diethyl ether, monoethyl ether, monoglyme, diglyme, ethyleneglycol, or the like), and heated to about 65-70° C. for about 1 hour.About 1.1 to about 1.3 moles (e.g., 1.2 moles) of Compound 2 is used permole of Compound 1. At the end of the reaction, the product is notisolated, and is used in-situ for the next step.

The structure of Compound 4 is novel. Compound 4 is prepared by reactingCompound 3 (obtained in-situ above) with a base (e.g., potassiumtert-butoxide, potassium pentoxide, potassium tert-amylate, sodiumethoxide, sodium tert-butoxide, or the like) in an alcoholic solvent(e.g., anhydrous EtOH). A catalytic amount of base is preferably used,generally, about 5-20 mol % per mol of Compound 3 in the alcoholicsolvent. More preferably, about 15 mol % of base is used. Preferably,the reaction mixture is heated to about 75-85° C. for about 1 hour. Atthe end of reaction, the product is not isolated, and is used in-situfor the next step.

The structure of Compound Salt 5K is novel. Compound 4 can be convertedto Compound Salt 5K by reacting it in-situ with from about 1 to about 3moles (e.g., 1.5 moles) of a N—R²-substituted carbamate, R²NHCO₂R¹(e.g., the urethane EtNHCO₂Et), and from about 1 to about 3 moles (e.g.,2.1 moles) of a base (e.g., potassium tert-butoxide, potassiumpentoxide, potassium tert-amylate, sodium ethoxide, sodiumtert-butoxide, or the like), in an ethereal organic solvent (e.g., THF,diethyl ether, monoethyl ether, monoglyme, diglyme, ethylene glycol, orthe like) or a sulfolane, at 80-130° C. (preferably 115-125° C.),wherein R¹ and R² are each independently defined as above. The baseprovides a metal ion (M⁺) to Compound Salt 5K. Potassium tert-butoxideprovides a potassium ion (K⁺), while sodium tert-butoxide provides asodium ion (Na⁺) to Compound Salt 5K. The inventive methodology providesan efficient synthesis for directly converting (in one step) Compound 4to Compound Salt 5K in solution without the use of any toxic chemicalsor harsh thermal conditions.

The potassium Compound Salt 5K is isolated by filtration, but not dried.Compound Salt 5K is selectively N-3 alkylated in-situ to Compound 6 withBrCH₂-L (e.g., 2-bromoethyl acetate in an anhydrous, organic solvent(e.g., THF, methyl tert-butyl ether, or the like) in the presence of aphase transfer catalyst (e.g., tetrabutylammonium bromide,tetrabutylammonium hydrogen sulfate, or the like), wherein L is definedas above. The reaction takes place rapidly (e.g., about 1 hour at about65-70° C.), and no base is required. This is in contrast to knownN-alkylation reactions, many of which use dimethylformamide (“DMF”) andpotassium carbonate or an organic base (e.g., triethylamine,diisopropylethylamine, etc.) to achieve the N-alkylation, and whichgenerally take from several hours to days to complete.

Alternatively, the potassium Compound Salt 5K can be neutralized with anacid (e.g., aqueous acetic acid, dilute hydrochloric acid, dilutesulfuric acid, or the like) to provide Compound 5. Under thisalternative process, Compound 5 can be selectively N-3 alkylated bytreatment with an inorganic base (e.g., potassium carbonate, sodiumcarbonate, sodium bicarbonate, potassium butoxide, or the like) in apolar solvent (e.g., acetonitrile and its higher homologs, DMF,N,N-dimethylacetamide (“DMA”), 1-methyl-2-pyrrolidinone (“NMP”), or thelike) in the presence of a phase transfer catalyst (e.g.,tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, or thelike) and an alkylating agent (e.g., BrCH₂-L, where L is defined asabove) to provide Compound 6.

The structure of Compound 6 is novel. The conversion from Compound 1 toCompound 6 is a 5-step process that can be carried out in one pot orcontainer. The overall yield for Compound 6 is generally about 45-55%.

The structure of Compound 7 is novel. Compound 6 is regioselectivelydihalogenated (e.g., dibrominated or dichlorinated) to Compound 7 undermild conditions with about 2-3 moles (preferably, about 2.7-2.8 moles)of a dihalogenating agent (e.g., a dibrominating agent, such as N-bromosuccinimide (“NBS”), dibromo-1,3-dimethyl hydantoin or N-bromoacetamide). The use of a strong acid (e.g., triflic or sulfuric acid) asa catalyst in an amount of about 1-10 mol %, preferably, about 3 mol %,allows the reaction to proceed at room temperature. Alternatively,tetrabutylammonium hydrogensulfate can be used as the catalyst, but itwould require an application of heat (e.g., about 80° C.) to drive thereaction to completion. It is preferred that the reaction is run in adry polar solvent, such as acetonitrile, DMF, NMP, DMA, or a mixturethereof. Under these conditions, the amounts of mono- and tri-bromo sideproducts are minimized.

Compound 7 is coupled with Compound 8 (an R⁴NH₂ amine) to form Compound13 via Compound 9, a novel intermediate. Typical coupling reactionconditions for this step generally require the use of a polar, aproticsolvent (e.g., NMP, DMA, or the like), an inorganic base (e.g.,potassium carbonate, sodium carbonate, sodium bicarbonate, or the like),and an excess of Compound 8, preferably, up to about 3 moles of Compound8 per mole of Compound 7. A preferred mild, inorganic base is sodiumbicarbonate. The application of heat will drive the reaction tocompletion faster. For example, at about 130-140° C., the reaction timecan be shortened in half, from about 24 hours to about 12 hours.

L is R³ or a protected form of R³ (i.e., where a moiety is attached toR³ for protecting it from reacting with other ingredients). When L isthe same as R³, Compound 9 is the same as Compound 13, so the additionof an inorganic base to the intermediate Compound 9 (step (k) (ii) ofthe summary of the invention) is not necessary. On the other hand, whenL is a protected form of R³, deprotection can be accomplished in thesame pot, without isolating Compound 9, by using a catalytic amount ofan inorganic base (e.g., potassium carbonate, tetrabutylammoniumhydroxide, or the like). Protected forms of R³ include R³ moietiessubstituted with protective groups such as acetate, propionate,pivaloyl, —OC(O)R⁵, —NC(O)R⁵ or —SC(O)R⁵ groups, wherein R⁵ is H orC₁₋₁₂ alkyl. When the protecting substituent is an acetate group,deprotection is preferably carried out with tetrabutylammonium hydroxidebecause it results in a faster and cleaner reaction, and productisolation is facile. In another embodiment of the invention, a pivaloylprotecting group can be used in place of the acetate protecting group,and the application of similar chemistry will lead from Compound 5K (orCompound 5) to Compound 13. The deprotection and work-up conditions areadjusted so as to minimize formation of isomeric impurities. Forinstance, care should be taken to monitor the basicity of the reactionduring deprotection because when the deprotection steps are carried outunder very strong basic conditions, diastereomers may form.

Specific Synthesis

The general synthesis of Scheme I can be applied to prepare specificxanthines. For example, if R¹ is —OCH₃, R² is —CH₂CH₃, L is —CH₂CO₂CH₃,R³ is —CH₂OH, and R⁴ is

,then the product obtained from Scheme I (Compound 13) can be called1-ethyl-3,7-dihydro-8-[(1R,2R)-(hydroxycyclopentyl)amino]-3-(2-hydroxyethyl)-7-[(3-bromo-4-methoxyphenyl)methyl]-1H-purine-2,6-dione(Compound 13A), a PDE V inhibitor useful for the treatment of erectiledysfunction. An illustration of this synthesis is shown in the followingScheme II, which allows for an efficient, commercial scale preparationof Compound 13A, without the need for chromatographic purification ofintermediates:

The experimental conditions disclosed herein are preferred conditions,and one of ordinary skill in the art can modify them as necessary toachieve the same products.

EXAMPLES Compound 1A: glycine-N-[(4-methoxyphenyl)methyl]ethyl ester

To a mixture of glycine ethyl ester hydrochloride (about 1.4 equiv) andpotassium carbonate (about 1.0 equiv) was added anhydrous ethanol. Themixture was stirred at about 40-45° C. for about 3 hours. Then,p-anisaldehyde (about 1.0 equiv.) was added, and the reaction mixturewas stirred for a minimum of about 3 hours to provide an imine (notshown). Upon reaction completion (about ≦5.0% p-anisaldehyde remainingby GC analysis), the reaction mixture was cooled to about 0-10° C. Then,an aqueous solution of sodium borohydride (about 0.50 equiv) was addedto the reaction mixture at a temperature of between about 0° C. andabout 20° C., and stirred for about 1 hour to provide Compound 1A. Uponcompletion of the reduction reaction, the reaction mixture was quenchedwith the slow addition of an aqueous solution of aqueous glacial aceticacid. After quenching, the reaction mixture was warmed to roomtemperature and filtered to remove solids. The filtrate was thenconcentrated under vacuum, followed by the addition of toluene and waterto facilitate layer separation. Aqueous potassium carbonate solution wasadded to adjust the pH of the mixture to about 8-9. The organic layerwas separated and the aqueous layer was extracted with toluene. Thecombined toluene extracts were concentrated to provide the product inabout a 80-85% yield (based on GC and HPLC in solution assay).

¹H NMR 400 MHz (CDCl₃): δ 7.23 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz,2H), 4.17 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 3.73 (s, 2H), 3.38 (s, 2H),1.88 (s, br, 1H), 1.26 (t, J=7.1 Hz, 3H); ¹³C NMR 100 MHz (CDCl₃): δ172.8, 159.2, 132.0, 129.9, 114.2, 61.1, 55.6, 53.1, 50.4, 14.6.

Compound 2: N-cyanomethanimidic acid ethyl ester

To cyanamide (about 1.2 mole) was added triethylorthoformate (about 1.33mole), and the reaction mixture was heated to about 85-95° C. forapproximately 2 hours to form Compound 2. Estimated in-solution yieldwas about 95-100%. The product was optionally purified by vacuumdistillation.

¹H NMR 400 MHz (CDCl₃): δ 8.38 (s, 1H), 4.28 (t, J=6.7 Hz, 2H), 1.29 (t,J=6.8 Hz, 3H); ¹³C NMR 100 MHz (CDCl₃): δ 171.5, 113.4, 65.5, 13.1.

Compound 3A: cis- and trans-glycineN-[(cyanoimino)methyl]-N-[(4-methoxyphenyl)methyl]ethyl ester

A solution of Compound 1A (about 1.0 mole) in toluene was concentratedunder vacuum to distill off toluene. Anhydrous tetrahydrofuran (“THF”)was added to the concentrate, then Compound 2 (about 1.2 moles, obtainedabove) was added to that, and the solution was heated at reflux forabout 1 hour. At this stage, the formation of Compound 3A was complete.Estimated in-solution yield was about 95% (about 2:1 mixture of cis andtrans isomers).

Compound 4A: 1H-imidazole-5-carboxylic acid,4-amino-1-[(4-methoxyphenyl)methyl]ethyl ester

Compound 3A (obtained above) was concentrated by distilling off THF.Then, anhydrous ethanol was added to afford a reaction mixture solution.Separately, potassium t-butoxide (about 0.15 mole) was dissolved inanhydrous ethanol to afford a solution. The potassium t-butoxidesolution was added to the reaction mixture solution and heated to about75-85° C. for about 1 hour. The overall in-solution yield of Compound 4Awas about 85-90%.

¹H NMR 400 MHz (CDCl₃): δ 7.16 (s, 1H), 7.08 (d, J=8.6 Hz, 2H), 6.82 (d,J=8.7 Hz, 2H), 5.23 (s, 2H), 4.93 (s, br, 2H), 4.23 (q, J=7.1, 2H), 3.76(s, 3H), 1.26 (t, J=7.1 Hz, 3H); ¹³C NMR 400 MHz (CDCl₃): δ 160.9,159.2, 139.0, 128.6, 128.5, 114.0, 101.8, 59.5, 55.2, 50.1, 14.4.

Compound 5AK:1-ethyl-3,7-dihydro-7-[(4-methoxyphenyl)methyl]-1H-Purine-2,6-dionepotassium salt

The reaction mixture containing Compound 4A in ethanol (obtained above)was added to diglyme and distilled under vacuum to remove the ethanol.After being cooled to room temperature, N-ethylurethane (about 1.2equiv.) was added and the reaction mixture was heated to about 110-120°C. A solution of potassium t-butoxide (2.2 equiv.) in diglyme was addedto the hot solution. The reaction mixture was cooled to roomtemperature. THF was added to precipitate additional product, which wasfiltered and washed to provide Compound Salt 5AK in 55-65% overallyield. The wet cake can be used as such for conversion to Compound 6A.

¹H NMR (DMSO-d₆, 400 MHz): δ 7.73 (s, 1H) 7.31 (d, J=8.6 Hz, 2H) 6.86(d, J=8.6 Hz, 2H) 5.24 (s, 1H) 3.88 (q, J=6.8 Hz, 2H) 3.71 (s, 3H) 1.07(t, J=6.8 Hz, 3H); ¹³C NMR (DMSO-d₆, 100 MHz): δ 161.1, 159.0, 158.4,157.2, 141.4, 131.0, 129.5, 114.1, 105.6, 55.4, 48.2, 34.4, 14.3.

Optional Neutralization of Compound Salt 5AK to Compound 5A:

Compound 5A:1-ethyl-3,7-dihydro-7-[(4-methoxyphenyl)methyl]-1H-Purine-2,6-dione

The wet cake filtered solid of Compound Salt 5AK (obtained above) wassuspended in water and then acidified to a pH of about 5 using glacialacetic acid. The resulting slurry was filtered to obtain the neutralizedproduct, which was then washed with water and dried. The overallisolated yield of neutralized Compound 5A from Compound 1A was about45-55%. Spectroscopic data for neutralized Compound 5A was identical tothat of Compound Salt 5AK.

Compound 6A:3-[2-(acetyloxy)ethyl]-1-ethyl-3,7-dihydro-7-[(4-methoxyphenyl)methyl]-1H-purine-2,6-dione

To the wet cake filtered solid of Compound Salt 5AK (obtained above)were added tetrabutylammonium bromide (about 0.05 mole) and 2-bromoethylacetate (about 1.2 moles) in THF. After being heated to reflux for about2 hours, part of the THF was distilled off, and isopropyl alcohol wasadded to the reaction mixture. The reaction mixture was thenconcentrated under reduced pressure and cooled to around roomtemperature. Water was added to precipitate the product. After beingcooled to about 0-5° C. for about a few hours, the product was isolatedby filtration. The wet cake was washed with aqueous isopropyl alcohol(about 30% in water), and dried under vacuum to afford Compound 6A as apale yellow solid in about a 45-55% overall yield (based on Compound1A). The crude product may be purified further by decolorizing withDarco in methanol, followed by filtration and concentration to affordcrystalline Compound 6A.

¹H NMR (CDCl₃, 400 MHz): δ 7.54 (s, 1H) 7.32 (d, J=8.6 Hz, 2H) 6.90 (d,J=8.6 Hz, 2H) 5.43 (s, 2H) 4.41 (m, 2H) 4.38 (m, 2H) 4.10 (q, J=7.2 Hz,2H) 3.79 (s, 3H) 1.96 (s, 3H) 1.25 (t, J=7.2 Hz, 3H); ¹³C NMR (CDCl₃,100 MHz): δ 171.1, 160.2, 155.3, 151.4, 148.9, 140.9, 130.1, 127.7,114.8, 107.5, 61.7, 55.6, 50.2, 42.4, 36.9, 21.2, 13.6.

After Optional Neutralization of Compound Salt 5AK to Compound 5A:

Compound 6A:3-[2-(acetyloxy)ethyl]-1-ethyl-3,7-dihydro-7-[(4-methoxyphenyl)methyl]-1H-purine-2,6-dione

Acetonitrile was added to a mixture of Compound 5A (about 1.0 mole),anhydrous potassium carbonate (about 1.5 moles) and tetrabutylammoniumhydrogen sulfate (about 0.05 mole). 2-bromoethyl acetate (about 1.5moles) was added in three separate portions (0.72 mole in the beginning,another 0.45 mole after about 2 hours of reaction, and then theremaining 0.33 mole after about another 1 hour of reaction) during thecourse of the reaction at about 80-85° C. The total reaction time wasabout 7 hours. The reaction mixture was cooled to about room temperatureand filtered. The filtrate was concentrated. Aqueous isopropanol wasadded to crystallize the product. The product was filtered, washed withaqueous isopropanol, and dried to provide Compound 6A in about a 75-80%yield.

Compound 7A:8-bromo-1-ethyl-3-[2-(acetyloxy)ethyl]-3,7-dihydro-7-[(3-bromo-4-methoxyphenyl)methyl]-1H-Purine-2,6-dione

Compound 6A (about 1 mole) and NBS (about 2.8 moles) were dissolved indry acetonitrile and agitated at about 15-20° C. To this reactionmixture, a solution of sulfuric acid (about 0.03 mol) in acetonitrilewas added, while maintaining the reaction temperature below about 25° C.The reaction mixture was agitated at about 20-25° C. for about 12-15hours until complete consumption of the starting material was indicated.The reaction mixture was cooled to about 0-5° C. and a cold (about 5-10°C.) aqueous solution of sodium sulfite was added, keeping thetemperature below about 10° C. The reaction was agitated for about 2hours at about 0-10° C., and then filtered. The isolated cake was washedwith water, followed by methanol, then dried under a vacuum to obtainCompound 7A in about an 85% yield.

¹H NMR (CDCl₃, 400 MHz): □ 7.60 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.4 Hz,2.0 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 5.43 (s, 2H), 4.35 (m, 4H), 4.05(q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.96 (s, 3H), 1.23 (t, J=7.0 Hz, 3H);¹³C NMR (CDCl₃, 100 MHz): □ 171.0, 156.2, 154.2, 150.8, 148.2, 138.3,128.9, 128.7, 127.5, 112.1, 112.0, 109.1, 61.5, 56.5, 49.3, 42.5, 37.0,21.0, 13.3. MS (ES) m/e 545.2 (M+H)⁺.

Compound 13A:1-ethyl-3,7-dihydro-8-[(1R,2R)-(hydroxycyclopentyl)amino]-3-(2-hydroxyethyl)-7-[(3-bromo-4-methoxyphenyl)methyl]-1H-purine-2,6-dione

Compound 7A (about 1 mole) was combined with(R,R)-2-amino-1-cyclopentanol hydrochloride (Compound 8A, about 1.2moles) and sodium bicarbonate (about 3 moles). To this reaction mixturewas added N,N-dimethylacetamide (“DMA”), and the reaction mixture wasagitated at about 135-140° C. for about 15-17 hours until completeconsumption of the starting material was indicated. Compound 9A is anintermediate that is formed, but not isolated, from the reactionmixture. The reaction mixture was then cooled to about 45-50° C., andtetrabutylammonium hydroxide (about 0.05 moles of about a 40% solutionin water) was charged therein, followed by methanol. The reactionmixture was refluxed at about 80-85° C. for about 8-9 hours untilcomplete deprotection of the acetate group was indicated. The reactionmixture was cooled to about 40-45° C. and concentrated under vacuum. ThepH of the reaction mixture was adjusted to about 5-6 with dilute aceticacid, and the reaction mixture was heated to about 55-65° C., and seededwith a small amount of Compound 13A. The reaction mixture was thencooled to about 30-35° C. over a period of about 2 hours, and water wasadded over a period of about 1 hour. The reaction mixture was furthercooled to about 0-5° C. over a period of about 1 hour, and agitated atthat temperature for about 4 hours. The Compound 13A product wasisolated by filtration, washed with water and dried to provide about an85-90% yield.

¹H NMR (CDCl₃, 400 MHz): □ 7.47 (d, J=2.1 Hz, 1H), 7.18 (dd, J=8.4 Hz,2.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.23 (s, 2H), 5.01 (s, 1H), 4.22(m, 2H), 4.15 (m, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.93 (m, 3H), 3.88 (s,3H), 3.77 (m, 1 H), 2.95 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.60-1.80(m, 4H), 1.35 (m, 1H), 1.23 (t, J=7.0 Hz, 3H); ¹³C NMR (CDCl₃, 100 MHz):□ 156.2, 154.0, 153.5, 151.8, 148.3, 132.6, 129.1, 127.9, 112.5, 103.2,79.5, 77.8, 63.2, 61.3, 56.7, 46.5, 45.9, 36.8, 32.9, 31.5, 21.4, 13.8.MS (ES) m/e 523.4 (M+H)⁺.

Micronization

Materials prepared by the above-described processes without furtherprocessing can exhibit particle sizes that are greater than optimal forpurposes of bioabsorption, and thus, bioavailability. In certainpreferred embodiments of the invention, the compounds disclosed hereinare subject to a micronization process to generate particle sizedistributions more favorable for bioabsorption.

Form 2 of Compound 13 (disclosed in the co-pending patent application“Xanthine Phosphodiesterase V Inhibitor Polymorphs,” incorporated byreference thereto) was micronized on a fluid energy mill (Jet PulverizerMicron Master, model 08-620). A feeder (K-Tron Twin Screw Feeder) wasused to feed material to the mill at a rate of about 80 grams/min. Amill jet pressure of 110 psig was used. The resulting material was thenheated to convert amorphous material generated during micronization tocrystalline material. The setpoint on the dryer (Stokes Tray Dryer,model 438H) was set to 95° C. The batch was heated at a temperaturebetween 90 and 100° C. for 8 hours. Differential Scanning Calorimetry(“DSC”) analysis indicated no amorphous material was present. Theparticle size distribution of the resulting material was characterized,using a Sympatec particle size analyzer, as having a volume meandiameter of 8.51 μm and a median particle diameter of 5.92 μm. Cryogenicmicronization processes may result in even more favorable particle sizedistributions.

The above description is not intended to detail all modifications andvariations of the invention. It will be appreciated by those skilled inthe art that changes can be made to the embodiments described abovewithout departing from the inventive concept. It is understood,therefore, that the invention is not limited to the particularembodiments described above, but is intended to cover modifications thatare within the spirit and scope of the invention, as defined by thelanguage of the following claims.

1. A method for producing a compound of formula 13A:

the method comprising: (i) reacting a compound of formula 7 with aprimary amine Compound of Formula 8 or a hydrochloride salt thereof, inthe presence of a base to form a compound of formula 9:

wherein L is a protecting group which is acetate, propionate, a pivaloylprotecting group, —OC(O)R⁵, or —NC(O)R⁵, wherein R⁵ is H or C₁₋₁₂ alkyland, wherein R⁴ is alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,aryl or heteroaryl, and R⁴ is optionally substituted with one or morehalo, nitro amino, or —C(O)OR⁵⁰ substituents, wherein —R⁵⁰ is H, Alkyl,cycloalkyl, heterocycloalkyl, heteroaryl or aryl; and (ii) treating thecompound of formula 9 with a base to remove the protecting group therebyforming a compound of Formula 13A wherein Compound 7 is Compound 7A,Compound 8 is Compound 8A, Compound 9 is Compound 9A and the base instep (i) is sodium bicarbonate, and wherein the reaction is carried outin the presence of N,N-dimethyl acetamide as a solvent: according to thefollowing scheme

wherein, DMA is N,N-dimethyl acetamide Me is CH₃—; and OAc is acetate.2. The method of claim 1 wherein said compound of formula 7A is preparedby dihalogenating a compound of formula 6A in accordance with thereaction scheme:

wherein said reaction scheme comprises dibrominating Compound 6A usingN-bromosuccinimide in acetonitrile as a solvent and sulfuric acid as acatalyst and wherein: MeCN is acetonitrile: NBS is N-bromosuccinimide,Me is CH₃—; and QAc is acetate.
 3. The method of claim 1 wherein thebase in step (ii) is tetrabutylammonium hydroxide, the addition of whichis followed by the addition of methanol:

wherein, n-BU4NOH is tetrabutylammonium hydroxide; Me is CH₃—; and OAcis acetate.